ABSTRACT The objectives of the Genomics Core are 1) to perform prospective and retrospective molecular analysis of prostate tumors, cell-free DNA (cfDNA) and germline DNA to facilitate the aims of the P01 and 2) to facilitate sharing of genomic data and linked clinical annotation among the P01 investigators and with the broader scientific community. To achieve these objectives, the Genomics Core includes personnel trained in cancer genetics, surgical pathology, biostatistics, bioinformatics, and genomic data sharing. The Genomics Core has three aims. First, to aid in the identification of germline mutations associated with increased heritable risk or poor long-term clinical outcomes, the Genomics Core will conduct targeted sequencing of 250 DNA damage repair (DDR) pathway genes or WES of prostate cancer tumors and matched germline DNA (Project 1) from men with prostate cancer for whom we have long-term clinical outcomes data. To further facilitate the identification of novel germline mutations that associate with increased heritable risk or poor clinical outcomes, all sequencing data generated as part of this P01 will be integrated in real-time with published datasets and unpublished genomic data from ongoing profiling initiatives at Memorial Sloan Kettering Cancer Center (MSK- IMPACT) and Dana-Farber Cancer Institute (DFCI-Profile). Second, the core will explore mechanisms of treatment resistance by analyzing tumors and cfDNA collected before and after PARP inhibitor treatment from patients enrolled on the MetaCURE clinical trial platform (Project 2). This latter aim required the Genomics Core to develop a cfDNA assay (MSK-ACCESS) that could be used to monitor patients for minimal residual disease and could also identify mutations that mediate response and resistance to PARP inhibition. Third, the core will facilitate data sharing both within the P01 and with the broader research community, including the NCI. All three research projects are highly integrated with and rely extensively on the Genomics Core to achieve their proposed aims. More specifically, the core will assist Project 1 by sequencing (targeted and whole exome) germline and, in some cases, matched tumor DNA from several large cohorts of annotated patient samples to identify alterations in DDR pathway genes. The core will also provide real-time access to the germline data generated by MSK-IMPACT and DFCI-Profile. The core will assist Project 2 by screening patients for DDR aberrations and with the analysis of tumor samples and cfDNA collected before and after PARP inhibitor treatment to monitor treatment response and to explore mechanisms of drug resistance. The core will work with Project 3 to perform molecular analyses of cells engineered to harbor deleterious BRCA2 or ATM alleles or in which ATM or CDH1 have been deleted. Finally, the Genomics Core will help all three projects make predictions about the pathogenicity of individual mutations to facilitate data interpretation, study enrollment, and prioritization of mutants for functional characterization.